Jugular vein inserted central venous catheters ( <scp>CVC</scp> ) and the risk of <scp>CVC</scp> ‐related bloodstream infections in patients with hematological malignancies
Authors: Enrico Schalk, Lena M. Biehl, Boris Böll
Journal: American Journal of Hematology (2022)

To the Editor: Heidenreich and colleagues described the insertion of central venous catheters (CVC) in the jugular vein (JV) as a main risk factor for CVC-related bloodstream infections (CRBSI) in patients with hematological malignancies.1 This conclusion was based on a retrospective single-center study on 153 CVC in patients with high-dose chemotherapy for autologous hematopoietic stem cell transplantation (HSCT) or induction or consolidation chemotherapy for acute leukemia between January 2011 and June 2013. They compared CVC inserted in the JV (94; 61.4%) with CVC inserted in the subclavian vein (SV; 59; 38.6%). In total, 10 CRBSI cases were diagnosed, the CRBSI rate for JV-CVC was 9.6% (9/94) compared to 1.8% (1/59) for SV-CVC (p = .055). The corresponding CRBSI incidences were 5.7 CRBSI/1000 CVC days versus 1.2 CRBSI/1000 CVC days (no significance testing provided). In a univariate analysis, only the JV insertion site was identified as a risk factor for CRBSI (hazard ratio [HR] 5.405 [95% confidence interval {95% CI} 0.68–50.0]; p = .036); a multivariate analysis was not performed.1 These results and, in particular, their strong interpretation raise some questions. Firstly, it is uncommon that, among other factors, not even neutropenia could be identified as a CRBSI risk factor. In stark contrast with the findings by Heidenreich et al.,1 neutropenia is a well-established and important risk factor for CRBSI in patients with acute leukemia, as described by Bodey et al. many decades ago.2 Furthermore, the advantage of SV-CVC regarding CRBSI risk is not clearly demonstrated so far despite several studies investigating CRBSI rates. A meta-analysis on 8501 CVC in ICU patients showed a comparable risk of CRBSI for JV and SV inserted CVC (risk ratio 1.16 [95% CI 0.57–2.36]).3 Accordingly, there is no preference in cancer patients for either jugular or subclavian as site of CVC insertion in evidence-based recommendations and guidelines, although femoral CVC insertions are discouraged.4 Notwithstanding the very limited sample size with a total of only 10 observed CRBSI, Heidenreich et al. draw a very far-reaching conclusions from their data when they state that the insertion site was the main risk factor for CVC-related complications in this patient population.1 Since there seem to be different statements regarding CRBSI risk for JV inserted CVC, we aimed to confirm the results provided by Heidenreich et al.1 in a different data set. We used data form the SECRECY registry (Study to Evaluate Central Venous Catheter-related Infections in Hematology and Oncology; German Clinical Trial Register [DRKS], no. DRKS00006551), an ongoing, clinical CRBSI registry starting in March 2013 in hematology and oncology departments, currently active in six German sites. Surveillance data are documented on CRBSI of non-selected, consecutive patients with short-term, non-tunneled JV, SV, or femoral vein CVC inserted for routine clinical use. All CVC were inserted according to local standard operating procedures. CRBSI were classified according to the 2012 Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO) definition.4 The registry was approved by the central ethics committee (Magdeburg University Hospital, approval no. 84/14) as well as by respective local ethics committees. Registry data entered until February 2022 on JV-CVC and SV-CVC ≥1 day in situ of patients with hematological malignancy as underlying disease including patients undergoing autologous or allogeneic HSCT were used for this analysis. Only CRBSI cases classified as definite CRBSI4 were considered in order to apply the same diagnostic criteria as used by Heidenreich et al.1 For direct comparison of both studies, we analyzed the same clinical and CVC parameters and endpoints respectively. Thus, we are able to directly compare our data with the Heidenreich study.1 As time to CRBSI was one of the primary endpoints in the Heidenreich study, we compare that endpoint and additionally compared CRBSI rate, CRBSI incidence, and cumulative CRBSI incidence at day 15 after CVC insertion (CRBSI15). Statistical analysis was performed using OpenEpi, version 3.01 (Atlanta, GA, USA, https://www.openepi.com), and IBM® SPSS® Statistics, version 28 (Armonk, NY, USA). The statistical tests used are shown in the tables. Two-sided p values <.05 were considered statistically significant. According to the inclusion criteria, we identified 3795 cases in the registry, including 220 SV-CVC (5.8%) (Table 1). Compared to the Heidenreich study,1 our cohort included fewer cases with acute myeloid leukemia. Furthermore, in our cohort, 410 CVC (10.8%) were antimicrobial-coated, compared to none in the Heidenreich study.1 On the other hand, only 1422 CVC (37.4%) had chlorhexidine gluconate (CHG)-coated dressings, while in the Heidenreich study all CVC were covered with CHG-coated dressings.1 5.405 (0.68–50.0) 1.269 (0.78–2.06) Our cohort included significantly more male patients in the JV-CVC group compared to the SV-CVC group (p = .016). In the JV-CVC group, the CVC time were significantly shorter (p < .001), and there were significantly fewer antimicrobial-coated CVC than in the SV-CVC cohort (p < .001). Interestingly, we found a trend toward a lower CRBSI rate in the JV-CVC cohort (5.2% vs. 8.2%; p = .064), but there were no statistically significant differences regarding CRBSI incidence (p = .211) or time to CRBSI (p = .338) as well as in the CRBSI15 (p = .480) (Table 1). To reduce the bias of co-variates, we additionally performed a matched-pair analysis, 1:1 matched for sex, diagnosis, CVC type, and CHG-coated dressing. Through this, 215 cases could be compared. We found no statistical difference neither for the CRBSI rate comparing JV-CVC with SV-CVC (11/215 [5.1%] vs. 18/215 [8.4%]; p = .248), nor for the CRBSI incidence (3.2 CRBSI/1000 CVC days vs. 4.5 CRBSI/1000 CVC days); p = .369), the time to CRBSI (HR 1.326 [95% CI 0.62–2.82]; p = .464) or the CRBSI15 (4.30% vs. 5.90%; p = .541) (Table 2). Taken together, our results are in contrast with the Heidenreich study.1 We found no significant difference in CRBSI rates between SV-CVC and JV-CVC and even observed a trend toward higher CRBSI rates in SV-CVC. These contraire results may be attributable to the low number of CVC cases or CRBSI events, respectively, in the Heidenreich study.1 Furthermore, the results of the retrospective and observational Heidenreich study1 are in contrast with results from a multicenter randomized controlled trial (RCT) on CRBSI regarding CHG-coated CVC dressings in neutropenic patients published 2016, the COAT trial.5 In this trial, CRBSI were significantly more frequent in patients with SV-CVC compared to JV-CVC (29/356 [8.1%] vs. 8/257 [3.1%]; p = .010). Importantly, the rate of CRBSI in the COAT trial were only cases of definite CRBSI,4, 5 which met the same diagnostic criteria as in our and in the study by Heidenreich et al.1, 4 Therefore, the results of these three discussed studies are comparable. However, it must be critically noted, that in the mentioned COAT trial the majority of SV-CVC were recruited from only one center (319/366; 87.2%).5 A center effect seems very likely here that could have impacted the results of this trial. In our study, more than a half of the documented SV-CVC came from one center (Tables 1 and 2), therefore a center effect cannot be ruled out. In the Heidenreich study, the great majority of patients suffered from acute leukemia (120/153 [78.4%]).1 This proportion was lower in our study (1900/3795 [50.1%]; Table 1) and in the COAT trial (279/613 [45.6%].5 This could indicate a difference in the duration of neutropenia in these studies, which could limit comparability of the data. Unfortunately, in our registry, the duration of neutropenia is not documented. However, we can provide indirect data on the duration of neutropenia: In the whole cohort, 335 cases neutropenia was present at both time-points, CVC insertion and CVC removal. Assuming initial neutropenia was continuous in these cases, the median duration of neutropenia was 13 days (interquartile range 8–22), which is in the range of median values in patients with acute leukemia. According to this assumptions, the CRBSI incidence per 1000 neutropenic CVC days was statistically not different between JV-CVC and SV-CVC in the whole cohort (p = .766) as well in the meta-analysis (p = .403) (Table 2). It is the nature of this non-controlled, real-world study that the procedures of CVC insertion and management of CVC as well as management of CRBSI were not uniform in the centers. Maybe this could have led to the different frequencies of CRBSI between the centers. In the whole cohort the CRBSI rate was 5.4% with a range of 1.5%–8.2% for all six centers; the CRBSI incidence was 3.3/1000 CVC days with a range of 0.9–6.8. Furthermore, the number of CVC documented in the registry varied between sites (159–1570, mean 633). Epidemiological data on CRBSI derived from RCT may reliably be transferred to real-world settings.6 However, to the best of our knowledge, there are no published RCT available so far comparing CRBSI rates of JV-CVC and SV-CVC in patients with hematological malignancies. Therefore, any evidence addressed here has to derive from secondary endpoints of RCT or from real-world multicenter studies, or registries, with adequate sample sizes. Based on the results of our large multicenter, registry-based (matched-pair) analysis presented here and the available studies so far, we think there is not enough evidence showing inferiority of jugular inserted CVC regarding CRBSI. In conclusion, the jugular CVC insertion site cannot be considered as the main risk factor for CRBSI in patients with hematological malignancies. Further investigations, ideally including in form of RCT, seem warranted. ES was involved in patient management, designed the study, collected and analyzed the data, and wrote the manuscript. LMB interpreted the data, revised the manuscript, and approved the final version of the manuscript. BB was involved in patient management, interpreted the data, revised the manuscript, and approved the final version of the manuscript. ES and BB thank all SECRECY staff for their great support and documentation. The authors received no financial support for the research, authorship, and/or publication of this article. ES reports no conflicts of interest relevant to this article. LMB reports no conflicts of interest relevant to this article. BB reports no conflicts of interest relevant to this article. Given the nature of routine clinical data and the anonymization of patient data, written informed consent was not required within the study. However, written informed consent was mandatory for procedures during clinical routine. The data that support the findings of this study are available from the corresponding author upon reasonable request.